Alkyl ethers of polyiodophenyl propionic acids



nitecl State ALKYL ETHERS OF POLYIODOPHENYL PROPIONIC ACIDS HelenFlorence Ginsberg, Montclair, and Domeniclr lfapa, Bloomfield, N.J.,assignors to Schering Corporanon, Bloomfield, N.J., a corporation of NewJersey No Drawing. Filed Dec. 28, 1953, Ser. No. 400,812 8 Claims. (Cl.260-519) This invention relates to a new group of compounds having X-raycontrast properties and to a process for manufacturing the same.

More particularly, the invention relates to polyiodi- (2) nated phenylfatty acids which contain a non-nuclear N02 lower alkoxy group andexhibit a specific selectivity for 20 I visualization of the gallbladder. om-oooNa oiH6ooHro0no The compounds of the present Inventioninclude the H acids of the following general formula: -OHO X NO: NH,

l I I H H H? H I01 I l R oni-o-ooorr o=o-oo0H my 1 01120-00011 CH .,oR2) IV OCzHs V CzHu I NH; NHOOCH: and their non-toxic metal and aminesalts, X being hydroxyl or amino, while R is a lower alkyl group, n isan I I A020 I I integer from 0-4 and'the group (CH2)nOR contains notmore than 7 carbon atoms. OHBOGOOH -CHiC-COOH The compounds of thepresent invention can be predorm i on pared from m-hydroxy benzaldehydeby the series of I I steps illustrated in the following equations: VIVII Hie-000m (RO(CH2)nOH1CO)20 CHO (CHM-OR oiLongornn-on oH I I H H; HI: H I I I C=CCOOH hydrolysis CHZ-(IJCOOH CHM-000E (moron 2)n OR I(Cam-0R II III The initial condensation of the m hydroxy benzaldehydecan be carried out 'with the alkali metal salts of the alkoxy-aliphaticacid in the presence of the alkoxyacid anhydride. Reduction of thecinnamic acid (II) may be carried out by any of the known catalytichydrogenation methods, such as hydrogen with Raneynickel catalyst in analkaline or alcoholic solution of the acid, or with platinum oxidecatalyst in an alcoholic solution of the acid, as well as by othermethods, such as by the use of sodium amalgam. After the reduction, mildalkaline hydrolysis regenerates the free nuclear hydroxyl group.

The iodination of the substituted propionic acid (HI) to the triiododerivative can 'be carried out by the use of the iodine-potassium iodidemethod in alkaline solution, or by the use of iodine monochloride" indilute acetic acid solution. Occasionally, both methods yield somediiodo compound, which is probably 2,4-disubsti- Patented Aug. 30, 19602 tuted. In this case, further iodinationof the diiodo-sub stancesyields the triiodo compound. The triiodo acids of this invention arecrystalline substances which are soluble in sodium bicarbonate solutionand also-in the usual organic solvents.

Preferably, all the compounds of general Formula I may be prepared byfirst reacting m-nitrobenzaldehyde with the appropriate acid anhydrideand sodium salt.- For example, reacting m-nitro benzaldehyde withethox-yacetic anhydride and sodium ethoxy-acetate in known manner yieldsu-ethoxy m-nitrocinnamic acid (IV), When IV is reduced in alkalinesolution in the presence of Raney-m'ckel, there is formeda-ethoxy-p-(3-aminophenyl)-pr0pionic acid (V) which, upon treatment withiodine monochloride, gives u-ethoxy- -(2,4,6-triiodo-3-aminophenyD-propionic acid (VI), in accordance with the followingequations:

Acylation of V1 with acetic anhydride, for example, yields thecorresponding acetylamino compound (VII). In similar manner, otheracylamino, for example the propionylamino and other lower aliphatic:acylamino, and also the benzoylamino derivatives of VI, and the sameacylamino derivatives of the other acids falling within Formula Iwherein X is NH can be obtained.-

The amino compound VI may be transformed into other compounds of generalFormula I by replacement of the amino group by hydrogen, hydroxyl" oriodine. These replacements are easily effected by converting VI into itsdiazonium salt and treating said diazonium salt with the appropriatereagent. For such conversions, for example, replacement by hydrogen maybe effected by refluxing the 'diazonium salt VIII with ethanol in thepresence of cuprous ion, or by treatment with hypophosphorus acid, togive a-ethoxy-p-(2,4,6-t1iiodophenyl) On the other hand, the diazoniumsalt VIII may be reacted with aqueous sulfuric acid, thereby effectingreplacement of the diazonium group by hydroxyl and yieldinga-ethoxy-fl-(2,4,6-triiodo-3-hydroxyphenyl) propionic acid (X).

reset I I H VIE P H1O CHzCCOOH However, we prefer not to subject theiodinated compounds to strong acid and thus prefer to diazotize V,followed by treatment with aqueous sulfuric acid to give compound [IIwhere n=0. Iodination of the hydroxy compound yields X as shown below.

9 N01 H 1C1 I Eff cleric-coon O C 2H6 Finally, the diazoniurn group maybe replaced by iodine, resulting in the formation of tetra-iodinatedcompounds of general Formula I, as illustrated below:

Although we prefer to carry out the Perkin condensation initially asindicated in the foregoing, it is possible, in some cases, to preparecompounds of general Formula I according to the following sequence:

CHO CHQCOONB NO: 11TH:

H, 101 ---e omen-coon -CHICHfl-COOH N H: NH:

I Br, I I H NaO 01m I VI OHIOHQOOOH OHifi -GOOH I l 15 xnr XIIIaReaction of m-nitrobenzaldehyde with sodium acetate and aceticanhydride, for example, affords in theusual manner, m-nitrocinnamic acid(XI); Hydrogenation of XI with Raney nickel or platinum oxide yields,B-(3-amino- 'phenyl) propionic acid (XII) which, upon iodination, gives{3-(2,4,6-triiodo-3-aminophenyl) propionic acid (XIII). Bromination inthe alpha position of XIII followed by treatment with sodium ethoxide,for example, results in the formation of u-ethoxy-fi-(2,4,6-triiodo-3-aminophenyl) propionic acid VI; This compound, which itself falls withinthe scope of this invention, may be converted to other compounds ofgeneral formula I by transformations heretofore described.

With m-hydroxybenzaldehyde as the starting material, the process ofobtaining compounds of this invention can be modified as follows:

4:0 fCHO p 7 I I I I Ha I 0130 on=oooorr I B)n R I I Withaminobenzaldehyde, initial iodination followed by condensation, andreduction, yields a further modified procedure represented by thefollowing equations:

By the procedures described hereinabove (see Equations 3 and 4), theintermediate XVIII on diazotization and bydrolysis will yield X. Y

Compounds of general Formula. I can be obtained also i by way of thesubstituted propionitrile as follows:

It is to be noted that compoundXX may be hydro lyzed to:

which can be used as an intermediate in some of the aforementionedprocesses.

The compounds of the present invention are preferably administered inthe form'of the free acids incorporated in tablets containing the usualbinders, such as starch, gums, sugar, and the like. They can also beadministered as the non-toxic metal salts, such as the sodium or calciumsalts, or as salts of non-toxic organic amines, such as mono-, di-, andtri-ethanolamines and the corresponding propanolamines, diethyl anddipropyl amines, and the like. Another very suitable pharmaceutical formfor the compounds of this invention is as a suspension of either thefree acids or the salts, such a suspension consisting of a 3 g. dose ofthe acid, and slightly more of the salt, corresponding to its greatermolecular weight. The powdered diagnostic agent can be dissolved orsuspended in milk, water, orange juice, or other potable liquid; whilethe free acids can also be put up in cc. ampules, suspended in watercontaining methylcellulose or kaolin, or in other suspending or .mtacidpreparations. With an oral dose of about 3 g., a satisfactory X-raypicture can be obtained in about 12 to 24 hours.

The following examples describe in greater detail, and by way ofillustration, satisfactory procedures for the preparation of thecompounds of this invention.

EXAMPLE I u-Eth0xy-5-(2,4,6 trii0d0-3-amin0phenyl) propionic acid Therequisite intermediate, ethoxyacetic anhydride, is prepared as follows:To a stirred solution of 104 g. of ethoxyacetic acid and 79 g. of drypyridine in 300 ml. of anhydrous ether at -10 is added dropwise asolution of 60 g. of thionyl chloride and 50 ml. of anhydrous ether. Thereaction temperature is maintained at l0 during the addition and themixture is stirred for an additional three hours, allowing thetemperature to rise to 0. After removing the precipitated pyridinehydrochloride by rapid filtration and washing with anhydrous ether, theether filtrate and washings are evaporated to a residue which isdistilled to yield ethoxyacetic anhydride.

A mixture of 25.2 g. of sodium ethoxyacetate, 114 g. of ethoxyaceticanhydride and 30.2 g. of m-nitrobenzaldehyde is stirred and heated at135-140" for 7 hours. The reaction mixture is cooled and poured into 1.0liter of water and the precipitated a-ethoxy-m-nitrocinnamic acid isremoved by filtration and purified by recrystallization from aqueousmethanol. (The substituted cinnamic acid can also be obtained by areaction in which the potassium'salt is substituted for the sodium saltof the ethoxyacetic acid: by the reaction of molar quantities ofethoxyacetic acid, triethylamine, m-nitrobenzaldehyde, and three molesof ethoxyacetic anhydride at -105 for 20 hours; or by the reaction ofethoxyacetic anhydride, triethylamine and m-nitrobenzaldehyde at 100-105for 20 hours.)

A solution of 0.1 mole of a-ethoxy-mmitrocinnamic acid in 100 ml. of 1-Naqueous sodium hydroxide is treated with hydrogen at 50-70 under 50 lbs.pressure in the presence of palladium-on-charcoal (5% or Raney nickelcatalyst. (The aqueous reduction may be run at higher pressures at roomtemperature in the presence of the above catalysts.- Hydrogenation ofthe free acid in ethanol solu tion in the presence of Adams platinumoxide affords the same product.) After removal of the catalyst byfiltration, the filtrate from the aqueous reduction is concentrated invacuo to about 25 ml., neutralized with concentrated hydrochloric acidand diluted to about 65 ml. with 6-N hydrochloric acid. To the stirredacid solution, previously heated to 70, are added 53.5 g. of iodinemonochloride in 125 ml. of 6 N-hydrochloric acid. After one hour, thereare added 270 ml. of water over a 15-minute period, while maintainingthe reaction temperature at 70 throughout. To the diluted solution thereare separately, but simultaneously, added 15 g. of iodine monochlorideand 500 ml. of water over a 5-hour period, after which the mixture iscooled and the crude acid removed by filtration. The solids aredissolved in dilute alkali, treated with sodium hydrosulfite, andprecipitated by the addition of a saturated solution of sodium chloride.The sodium salt is removed by filtration, dissolved in water andacidified by the addition of sodium bisulfite, whereupon the crude acidprecipitates and is removed by filtration. Recrystallization fromaqueous alcohol yields a-GthOXY-fi- (2,4,6-triiodo-3-aminophenyl)propionic acid.

EXAMPLE II- a-Methoxy-p-(2,4,6-triiodo -3-aminophenyl) propionic acidonic acid.

EXAMPLE HI a-n-Amyloxy-fl-(2,4,6-trii0d0-3-aminophenyl) propionic acidThe intermediate n-amyloxyacetic anhydride is obtained by the reactionof 292 g. of n-amyloxyacetic acid and 158 g. of anhydrous pyridine in650 ml. of anhydrous ether with g. of thionyl chloride in 50 ml. ofanhydrous ether below -10. The reaction mixture is allowed to stir for 5hours at 0 before the product is isolated as in Example I.

The requisite a-amyloxy-m-nitrocinnamic acid is obtained from 274 g. ofamyloxyacetic anhydride, 75 gfiof triethylamine and 75 g. ofm-nitrobenzaldehyde as in Example I. V Hydrogenation of 41.8 g.a-amyloxy-m-nitrocinnamic acid is carried out in ethanol solution at 750lbs. pres sure in the presence of Raney nickel catalyst. The reducedacid is iodinated as in Example I and the 11-11-amyloxy-p-(2,4,6-triiodo-3-aminophenyl) propionic acid purified byrecrystallization from benzene or chloroform.

EXAMPLE IV u-Methoxy-B-(2,4,6-Iriid0-3-hydr0xyphenlyl) propionic acidFifty milliliters of an aqueous solution containing 0.1 mole of sodiumot-methoxy-m-nitrocinnamate (obtained as in Example II) is hydrogenatedas in Example I. After filtration of the catalyst, 17 ml. ofconcentrated sulfuric acid are added to the filtrate, the solutioncooled to and diazotized with 6.7 g. of sodium nitrite in 25 ml. water,the temperature being kept below 5 throughout the reaction. The colddiazonium sulfate solution is added to a boiling solution of 500 ml.water, 41 m1. of concentrated sulfuric acid and 5 ml. of a saturatedcopper sulfate solution at such a rate that the temperature of theboiling solution remains above 90. When the evolution of nitrogen iscomplete, the solution is cooled and extracted with ether. The etherealsolution is washed with salt solution, dried over anhydrous sodiumsulfate and evaporated to yield a residue of crudewmethoxy-fi-(3-hydroxyphenyl) propionic acid which is used withoutfurther purification for the iodination.

To a stirred solution of the crude acid from the diazotization andreplacement in 130 ml. of glacial acetic acid is added 58 g. of iodinemonochloride in 80 ml. of acetic acid over a period of 1-1.5 hours.After 15 minutes, 400 ml. of water are added dropwise to the solutionand stirring is continued for an additional hour. The reaction mixtureis heated slowly to 80 and maintained at that temperature for 40minutes, then allowed to cool. The excess iodine monochloride isdestroyed by the addition of solid sodium bisulfite, and the iodinatedacid is filtered, washed with Water and purified by recrystallizationfrom acetone-water. The d-methoxy-B-(2,4,6-triiodo-3-hydroxyphenyl)propionic acid can also be obtained from the iodination of crude sodiuma-methoxy-3-hydroxy-hydrocinnamate with iodine-potassium iodidesolution.

Alternately, the a-methoxy-fl-(3-hydroxyphenyl) propionic acid canbeprepared as follows: Sodium methoxyacetate, methoxy-acetic anhydride andm-hydroxybenzaldehyde in a molar ratio of 1:3:1, are heated, withstirring, at 135-140" for 14 hours. After cooling, the reaction mixtureis poured into 4 volumes of water, the precipitated'a-methoxy-m-(acetoxy) cinnamic acid extracted with ether, the etherealsolution washed with salt solution, dried and evaporated to a residue.The residue is dissolved in a stoichiometric amount of dilute aqueousalkali and hydrogenated with Raney nickel catalyst at 50 lbs. pressureand room temperature. The catalyst is filtered off and additional alkaliadded to the filtrate and the solution is refluxed for several hours.The crude a-methoxy-B-hydroxyhydrocinnamic acid(ccmethoxy-B-(3-hydroxyphenyl) propionic acid) isolated from theethereal extract of the acidified hydrolysis solution is identical withthat obtained from the diazotization-replacement reaction firstdescribed in this example. Iodination of this crudea-methoxy-B-(m-hydroxyphenyl) propionic acid as above described in thisexample yields the same triiodo compound.

EXAMPLE V u-Ethoxy-fl-(2,4,6-trii0d0-3-hydroxyph enyl) acid propionicand the iodinated acid is recrystallized from aqueous alcohol.

EXAMPLE VI a Propoxy-B-(2,4,6-triiodo-3-hydroxyphenyl) propionic acida-n-Amyloxy-fl-(2,4,6-triiodo-3-hydroxyphenyl) propionic I acid Asolution of a-amyloxy-rn-nitrocinnamic acid (obtained as in Example III)in aqueous alkali is reduced, the aromatic amine group replaced byhydroxyl through diazotization and the crude n-n-amyloxy-m-hydroxyhydrocinnarnic acid iodinated as in Example IV. The obtained atn-amyloxy-B (2,4,6-triiodo-3-hydroxyphenyl) propionic acid is purifiedby recrystallization from aque ous acetone.

EXAMPLE VIII a- (2,4,6-triiod0-3-aminobenzyl) -fl-methoxy-pr0pi0nic acidThe required intermediate fi-methoxypropionic anhydride, is preparedfrom 1 mole of B-methoxypropionic acid as described in Example I. Thefurther intermediate ot-(m-nitrobenzal) -B-methoxy-propionic acid isobtained by the reaction of sodium fi-methoxypropionate,,B-methoxy-propionic anhydride and m-nitrobenzaldehyde, as described inExample I.

Hydrogenation of u-(rn-nitrobenzal)-fi-methoxy propionic acid in adilute alkaline solution in the presence of palladium-on-charcoalfollowed by iodination as in Example I, yields theu-(2,4,6-triiodo-3-aminobenzyl) 9- methoxy-propionic acid. The iodinatedacid is purified by recrystallization from aqueous alcohol.

EXAMPLE IX a (2,4,6-triiodo 3-hydroxyb'enzyl)-fi-methoxypropionic acidIodination of the crude a-(m-hydroxybenzyl)-B-methoxypropionic acidobtained through hydrogenation, diazotization and replacement ona-(m-nitrobenzaD-fimethoxypropionic acid (from Example VIII) as inExample IV, yields a-(2,4,6-triiodo-3-hydroxybenzyl) B- methoxypropionicacid, purified by recrystallization from aqueous alcohol. 4

EXAMPLE X a-(2,4,6-trii0d0-3-amin0benzyl) -B-ethoxypropionic acid Theintermediate fl-ethoxypropionic anhydride is prepared from one mole offl-ethoxypropionic acid as described in Example I. The furtherintermediate tZ-(mnitrobenzal) -;8-ethoxypropionic acid is obtained fromthe reaction of the fl-ethoxypropionic anhydride, triethylamine andm-nitrobenzaldehyde, as in Example I.

After the reduction of the a-(m-nitrobenzab-fl-ethoxypropionic acid indilute alkaline solution, the iodination is run without isolation of theintermediate reduction product, as given in Example I. Recrystallizationfrom aqueous alcohol yields a-(2,4,6-triiodo-3-arninobenzyl)-,B-ethoxypropionic acid,

EXAMPLE XI a-(2,4,6-triicdo-3-hydroxybenzyl)-fi-eth0xypr0pi0aic acidReduction of the a-(m-nitrobenzal)-[3-ethoxypropionic acid, obtainedaccording to Example X, followed by diazotization and replacement of theamino by hydroxy and iodination of the crude hydroxy acid, as in ExampleIV, gives the u-(2,4,6-triiodo-3-hydroxybenzyl)-fi-ethoxypropionic acid,which can be purified by recrystallization from alcohol and water.

EXAMPLE XII a-(2,4,6-triid0-3-amin0benzyl) -;8-n-but0xypr0pi0nic acidu-(2,4,6-trii0d0-3-hydr0xybenzyl) -,B-is0amyl0xypropi0nic acid Therequired Bdsoamyloxypropionic anhydride is'prepared from thecorresponding acid by reaction with pyridine and thionyl chloride, asdescribed in Example I. The anhydride is then converted intooi-(m-nitrobenzaD- S-isoamyloxypropionic acid by reaction withtriethylarnine and m-nitrobenzaldehyde, as in Example I.

After hydrogenation of the a-(m-nitrobenzal)-[3-isoamyloxypropionicacid, the crude amino compound is diazotized and treated with sulfuricacid, and thereafter iodinated, as in Example IV. Recrystallization fromacetone-water gives pure a-(2,4,6-triiodo-3-hydroxybenzyl)-,8-isoamyloxy-propionic acid.

EXAMPLE XIV a-(2,4,6-trii0d0-3-aminobeazyl)-- -meth0xybiztyric acid Theintermediate y-methoxybutyric anhydride is prepared from the-methoxybutyric acid as in Example I. There is then formed thea-(m-nitrobenzal)-'y-methoxybutyric acid through the Perkin reaction ofthe potassium salt of the acid, the anhydride and m-nitrobenzaldehyde,as in Example I.

After reduction of the a-(m-nitrobenzal)-'y-methoxybutyric acid inalkaline solution, the iodination is performed without isolation of theintermediate reduction product, as in Example I. Thea-(2,4,6-triiodo-3aminobenzyl y-methoxybutyric acid is purified byrecrystallization from aqueous alcohol.

EXAMPLE XV a- (2,4,6-zrii0d0-3-hydr0xybenzyl) ymethoxybatyric acidHydrogenation of a-(m-nitrobenzal)-'y-methoxybutyric acid (obtained asin Example XIV) followed by diazotization, replacement and iodination,as described in Example IV, yieldsa-(2,4,6-triiodo-3-hydroxybenzyl)-'y-rnethoxybutyric acid, which ispurified by recrystallization from aqueous alcohol.

EXAMPLE XVI The intermediate-q-ethoxybutyric anhydride is prepared fromthe corresponding acid as described in Example I. The anhydride is thenconverted into oz-(m-nitrobenzaD- 'y-ethoxybutyric acid via the Perkinreaction as in Example I.

10 The (it-(2,4,6 triiodo-3-aminobenzyl)- -ethoxybutyric acid isobtained from the reduction of the a-(m-nitrobenzal)-'y-ethoxybutyricacid followed by iodination, as in Example I. The iodinated acid isrecrystallized from aqueous acetone.

EXAMPLE XVII a-(2,4,6-trii0d0-3-hydroxybenzyl) -eihoxybatyric acidHydrogenation of a-(m-nitrobenzal)-' -ethoxybutyric acid (obtained as inExample XVI), reaction with sodium nitrite, then decomposition of thediazonium salt with hot sulfuric acid as in Example IV, yields the crudea-(mhydroxybenzyl)-'y-ethoxybutyric acid. Iodination of the crudehydroxy compound (as in Example IV) yields oc-(2,4,6triiodo-3-hydroxybenzyl)-'y-ethoxybutyric acid which is recrystallizedfrom benzene.

EXAMPLE XVIII a-(2,4,6-triiodo-3-aminobenzyl) -'y-but0xybutyric acid Theintermediate 'y-butoxybutyric anhydride is prepared from'y-butoxybutyric acid, pyridine and thionyl chloride, as described inExample I.

The requisite a-(rn-nitrobenzal) y-butoxybutyric acid is obtained fromthe reaction of the y-butoxybutyric anhydride, triethylamine andm-nitrobenzaldehyde, as described in Example I.

Reduction of an aqueous alkaline solution ofcz-(mnitrobenzal)-'y-butoxybutyric acid followed by iodination withiodine monchloride as in Example I, yields a(2,4,6triiodo-3-aminobenzyl)-'y-butoxybutyric acid, which is recrystallizedfrom benzene or chloroform.

EXAMPLE XIX u-(2,4,6-trii0d0-3-hydr0xybenzyl) w-propoxybulyric acid Therequisite intermediate -propoxybutyric anhydride is prepared from thecorresponding acid, as in Example I.

The requisite a-(m-nitrobenzal)w-propoxybutyric acid is obtained by thePerkin reaction, as in Example I.

Hydrogenation of the Perkin product followed by diazotization andreplacement of the amino group by hydroxy, then iodination (as inExample IV) yields tZ-(2,4,6- triiodo-3-hydroxybenzyl)w-propoxybutyricacid. The iodinated acid is recrystallized from aqueous alcohol.

EXAMPLE XX a-(2,4,6-triiad0-3-aminobenzyl)-5-methoxy valeric acid Theintermediate substituted valeric anhydride is prepared from the 8methoxy-valeric acid, as described in Example I.

The required a-(m-nitrobenzal)-5-methoxy-valeric acid is obtained fromthe reaction of 6 methoxy-valeric anhydride, triethylamine and m-nitrobenzaldehyde, as in ExampleI.

Reduction of the intermediate Perkin product followed by iodination asin Example I, yields a-(2,4,6-triiodo-3- aminobenzyl) 6 methoxy-valericacid which is recrystallized from aqueous alcohol.

EXAMPLE XXI a-(2,4,6-triiodo 3-hydroxybenzyl)-6-eth0xy valeric acid Therequired fi-ethoxyvaleric anhydride is obtained from the correspondingalkoxy acid, as in Example I.

The intermediate a-(m-nitrobenzal)-6-ethoxyvaleric acid is prepared bythe reaction of a-ethoxyvaleric acid, triethylamine, a-ethoxy valericanhydride and m-nitrobenzaldehyde, as in Example I.

Reduction of the intermediate a-(m-nitrobenzal) 5-ethoxy valeric acid,diazotization, replacement of the amino group by hydroxy and iodinationwith iodinemonochloride in acetic acid (as in Example IV) yieldsa-(2,4,6-triiodo- 3-hydroxybenzyl)-6-ethoxyvaleric acid, recrystallizedfrom benzene or chloroform.

. 11 EXAMPLE xxn a (2,4,6 triid0 3 aminozenzyl) e m-ethoxycaproio acidThe requisite S-butoxyvaleric anhydride is obtained from the fibutoxyvaleric acid, as described in Example I.

The requisite intermediate, a-(m-nitrobenzal)-6-butoxyvaleric acid isformed in the reaction of sodium fi-butoxyvalerate, 6-butoxyvalericanhydride and m-nitrobenzaldehyde, as in Example I. 7

Reduction of an aqueous alkaline solution ofe-(mnitrobenzal)-6-butoxyvaleric acid and iodination without isolationof the intermediate reduction product (as in Example I) givesa-(2,4,6-triiodo-3-aminobenzyl)-6-butoxyvaleric acid. The iodinated acidis purified by recrystallization from aqueous acetone.

EXAMPLE XXIII oz (2,4,6 triiodo 3 aminobewzyl) e methoxycaproic acid Therequired e-methoxycaproic au'hydride is obtained from the correspondingacid, as described in Example I. The anhydride is converted intoa(m-nitrobenzal)-emethoxyca-proic acid by reaction with triethylamineand m-nitrobenzaldehyde, as described in Example I.

After hydrogenation of the ot-(m-nitrobenzaD-e-methoxycaproic acid and.iodination, without isolation of the intermediate reduction product,the a-(2,4,6-triiodo-3- aminobenzyl)-e-methoxycaproic acid is obtainedand is recrystallized from aqueous alcohol.

EXAMPLE XXIV a (2,4,6 triiodo 3 lzydroxyben zyi) e ethoxycaproic acidThe requisite e-ethoxycaproic anhydride is prepared from thecorresponding acid by reaction with pyridine and thionyl chloride as inExample I.

The intermediate u-(m-nitrobenzal)-e-ethoxycaproic acid is obtained bythe reaction of potassium e-ethoxycaproate, e-ethoxycaproic anhydrideand m-nitrobenzal dehyde, as described in Example I.

After reduction of the' a-(m-nitrobenzal)-e-ethoxy caproic acid,diazotization and replacement of the amino group by hydroxy, andiodination with iodine monochloride in acetic acid, as described inExample IV, the a (2,4,6 triiodo 3 hydroxybenzyl) e ethoxycaproic acidis obtained. The iodinated acid is purified by recrystallization frombenzene.

EXAMPLE XXV 0c Methoxy (2,4,6 triiodophenyl) prapio'nic acid To avigorously stirred solution of 5.7 g. ofa-m'ethoxy-{3-(2,4,6-triiodo-3-aminophenyl) propionic acid (obtained asin Example II) in 50 ml. of concentrated sulfuric acid cooled to 0,there is added 0.75 g. of finely powdered sodium nitrite. After anadditional two hours at 0, the reaction mixture is poured on toapproximate- 1y 100 g. of ice, the temperature being kept below 5. Theslurry formed is gradually added to a cooled, vigorously stirredsuspension of 2.8 g. of cuprous oxide in 210 ml. of 95% ethanol. Whenthe initial evolution of nitrogen has subsided, the mixture is refluxeduntil no further nitrogen is evolved, then diluted with an equal volumeof water and allowed to remain overnight at room temperature. Filtrationof the precipitate followed by ether extraction of the solids, washingof the ethereal solution with sodium thi-osulfate solution andevaporation of the solvent yields a-meth oxy-,B(2,4,6-triiodophenyl)propionic acid, which is purified by recrystallization frombenzene-hexane.

12 EXAMPLE XXVI a-Methoxy-fl-(2,3,4,6-tetraiodophenyl) propionic acid Asolution of 5.7 g. of a-methoxy-B-(2,4,6-triiodo-3- aminophenyl)propionic acid (obtained as in Example II) is diazotized in 30 m1. ofconcentrated sulfuric acid with 2.1 g; of sodium nitrite as in ExampleXXV. A solution of 12.7 g. of potassium iodide in 28 ml. of water isadded to the cold aqueous slurry of the diazonium salt; and after theinitial vigorous reaction has subsided, the mixture is heated on thesteam bath for one hour. It is then poured into a cold sodium bisulfitesolution and the crude a-methoxy-fl-(2,3,4,6-tetraiodophenyl) propionicacid is filtered and recrystallized from acetonewater.

EXAMPLE XXVII a-Methoxy-fi-(2,4,6-trii0d0-3-mlethoxyphenyl) 'propionicacid A solution of 25 g. of the hydroxy compound obtained in Example IVin 250 ml. 10% sodium hydroxide is treated with 75 ml. of dimethylsulfate. At this stage the reaction mixture is diluted to 750 ml. and anadditional 25 ml. of dimethyl sulfate is added. The dimethyl sulfate isadded in such a manner that several times during the process thereaction mixture becomes slightly acid. After allowing the mixture tostand overnight, it is poured into 500 ml. of water whereupon solids areformed. The crude material is extracted with ether and the ether isdried and evaporated. Upon recrystallization of the residue fromalcohol, there is obtained the compound of this example.

In a similar manner the following compounds arepreparedza-ethoxy-fi-(2,4,6-triiodo-3-methoxyphenyl) propionic acid,a-propoxy-fl-(2,4,6-triiodo-3-methoxyphenyl) propionic acid,a-n-amyloxy-fl-(2,4,6-triiodo-3-methoxyphenyl) propionic acid,a-(2,4,6etriiodo-3-methoxybenzyl) -;8-rnethoxy propionic acid,ot-(2,4,6-triiodo-3-metl1- oxybenzyD-B-methoxy butyric acid.

In order to prepare alkoxy compounds other than methoxy, thecorresponding alkyl halide is used in place of the dimethyl sulfate. Itis advantageous to use 10% sodium hydroxide in 50% alcohol in order tomaintain all components in solution. Using the appropriate alkyl bromidethe following compounds are prepared:u-methoxy-fi-(2,4,6-triiodo-3-isopropoxyphenyl) propiouic acid,u-ethoxy-B-(2,4,6-triiodo-3-ethoxyphenyl) propionic acid, a 2,4,6 tniodo3 propoxybenzyl) ,8 methoxy propionic acid.

EXAMPLE XXVIII a Ethoxy 9 (2,4,6 triiodo 3 acetyloxyphenyl) propionicacid By reacting equimolar quantities of the compound obtained inExample V, acetyl chloride and pyridine in benzene solution there isobtained the acetyloxy compound of this example. The reaction mixture isrefluxed for several hours and upon cooling the acetyloxy compoundseparates. The crude product is removed by filtration, washed thoroughlywith water and recrystallized from aqueous alcohol.

In a similar manner there is obtained the propionyloxy, butyryloxy,benzoyloxy, by using the appropriate acyl halide in place of acetylchloride.

It is evident from the foregoing that treating the hydroxy compoundsdescribed in the foregoing examples with an acyl halide as abovedescribed yields the various acyloxy derivatives of this invention.

EXAMPLE XXIX a-Ethoxy-fl-(2,4,6-triiodo-3acetylaminophenyl) propionicacid A solution of 20 g. of the amino acid obtained from Example I in 50ml. of acetic anhydride containing 10 drops of concentrated sulfuricacid is heated on a steam bath for hours. The reaction mixture is pouredinto ice and warmed on a steam bath to hydrolyze the excess aceticanhydride. The solid material is removed by filtration andrecrystallized from ethyl acetate-acetone.

In a similar manner the following compounds are prepared:a-methoxy-B-(2,4,6-triiodo-3-acetyliminophenyl) propionic acid,a-(2,4,6-triiodo-3-acetylaminobenzyl)- fl-methoxy propionic acid.

It is evident from the foregoing that by employing anhydrides of otheracids such as propionic anhydride, butyric anhydride, and the like, thecorresponding acylamino compounds are obtained.

In each of the above examples, the obtained acids can be neutralized inknown manner with a metal base to form the metal salts, like the sodium,potassium, calcium and magnesium salts, or with an amine, such as any ofthose referred to hereinabove.

We claim:

1. A compound of the class consisting of acids of the formula H CHg-C-COOH (CHOHOR 14 and their alkali metal, alkaline earth metal, loweralkylamine and lower alkylolamine salts X being a member of the groupconsisting of hyd-roxy and amino, while R is a lower alkyl group, and n'is an integer from O to 2, the group (CH OR containing from 1 to 4carbon atoms, said compound on oral administration being effective invisualizing the gall bladder on X-ray examination.

2. Compounds as defined in claim 1, wherein X is OH. 3. Compounds asdefined in claim 1, wherein X is NH 4. Compounds as defined in claim 1,wherein m is 0. 5. Compounds as defined in claim 1, wherein n is 1. 6.Compounds as defined in claim 1, wherein n is 2. l7.a-Ethoxy-fi-(2,4,6-triiodo-3 aminophenyl) propionic acid.

8. a-Ethoxy-[H2,4,6-triiodo-3*hydroxyphenyl) onic acid.

propi- References Cited in the file of this patent UNITED STATES PATENTSArcher Apr. 5, 1955 OTHER REFERENCES Lewis et al.: J.A.C.S., vol. 71,pages 3753-5 (1949).

1. A COMPOUND OF THE CLASS CONSISTING OF ACIDS OF THE FORMULA 